PROJECT SUMMARY Hantaviruses are an emerging family of highly pathogenic viruses that cause 100-200,000 cases of two severe febrile illnesses a year; Hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). While the annual incidence of infections are relatively low compared to other viral infections, some hantavirus strains are particularly deadly, causing a 35-40% mortality rate in otherwise healthy young adults. In fact, because of their high mortality rates hantaviruses are considered a potential bioterrorism agent by the NIH, CDC and the Department of Defense. Coupled with the fact that there is no virus-specific treatment or globally approved vaccine to protect against infections, these emerging viruses represent a considerable threat to global public health. While there is no virus-specific treatment, evidence indicates that neutralizing antibodies (Abs) can control hantavirus infections in humans. Studies also show that some HFRS and HCPS patients possess Abs that can cross-neutralize heterologous strains. Thus, we hypothesize that some HPCS and HFRS convalescent patients evolve Abs that can broadly neutralize multiple hantavirus strains. Ichor Biologics has developed a platform for the isolation of naturally-occurring human monoclonal Abs (mAbs), which we have used to isolate several hundred hantavirus-specific mAbs from a cohort of HCPS convalescent patients. In characterizing these patients, we observed that some patients developed Abs that recognized a heterologous strain, suggesting that some patients may possess Abs that broadly neutralize multiple hantavirus strains. Therefore, the Product to be developed is a broadly neutralizing Ab(s) therapeutic to treat HCPS and HFRS caused by hantavirus infections. To examine the feasibility of this product, in aim 1 we will screen the hundreds of mAbs previously isolated from HCPS patients for their capacity to neutralize multiple hantavirus strains. This screen will be facilitated by a BSL2-safe, rapid hantavirus neutralization assay developed by Ichor Biologics. Since viruses can acquire mutations that allow them to evade Ab responses, in aim 2, we will determine the functional epitopes bound by any broadly neutralizing Abs in order to identify the Abs that can be combined into a therapeutic cocktail. These studies will determine the potential for developing a broadly neutralizing Ab-based therapeutic from hantavirus convalescent patients and accelerate the commercialization of any therapeutic for use in the clinic. Considering the high safety and efficacy profiles of biologics, plus our strong positioning in the hantavirus space (e.g. strong scientific, legal and business advisors, and Chilean government funding), we are uniquely situated to successfully develop and commercialize a broadly neutralizing Ab(s) therapeutic to treat HCPS and HFRS caused by hantavirus infections.